Therapeutic potential of mangiferin in cancer: Unveiling regulatory pathways, mechanisms of action, and bioavailability enhancements – An updated review

Abstract Mangiferin (MGF) is a phenolic compound, which is a major source of MGF is the mango tree. MGF possesses some antioxidant, anti‐inflammatory, and cytoprotective properties, enabling it to play its role against various diseases such as diabetes, obesity, lung injuries, and cancer. The word “Cancer” depicts an uncontrolled and abnormal growth of cells. This review paper reveals MGF's therapeutic, curative and protective potential impact against lung, liver, ovarian, prostate, breast, stomach, and oral cancers. MGF is used in various types of research in the form of powder, liquid extract, intramuscular, intravenous, nanoparticles coated with gold, in the form of a solution, or in combination with other drugs to evaluate synergistic effects. Many studies showed that MGF is safe to use but has less bioavailability in the body and 0.111 mg/mL solubility in water. However, certain studies indicated that its bioavailability and retention time increased when taken in the form of nanoparticles and in combination with other drugs. MGF also increases the sensitivity of other drugs (i.e., cisplatin) resistant to tumors. MGF has different mechanisms of action for different cancers. It mainly targets enzymes, interleukins, tumor growth factors, signaling pathways, apoptotic proteins, and genes to inhibit the growth of tumors, volume, angiogenesis, cellular functionality, further progression, and movement to other areas of the body. Moreover, MGF increases apoptosis and body weight with no or fewer side effects on normal cells. MGF unveiled a novel gate toward the treatment of cancer. Further research and human trials are needed in this regard.

The mango plant is grown throughout the world.At the same time, its crops are most common in tropical climates and subtropical climes (Lo Galbo et al., 2021), as well as in stifling areas of India, Africa, Asia, and Central America.MGF has grown in India's subcontinent for the last 4000 years and is abundantly used in Ayurvedic and traditional medical systems (Delgado-Hernández et al., 2020).
Among these are the Southern sections of the Italian Peninsula, such as Sicily, where mangoes have been grown for the past decade due to suitable pedoclimatic conditions (Lo Galbo et al., 2021).The major components of C. intermedia (a North American plant) extracts are xanthones (MGF) and flavanones (hesperetin and hesperidin), which are thought to be responsible for the majority of its pharmacological effects, including antidiabetic, anticancer, anti-obesity, antioxidant, antimicrobial properties (Aboyewa et al., 2021;Wani et al., 2022), and radioprotective activities (Shang et al., 2021).
MGF was widely employed in ancient Chinese medications due to its pharmaceutical activities (Rodriguez-Gonzalez et al., 2021;Xiao et al., 2021).The high content of macronutrients (carbohydrates and lipids), micronutrients (vitamins and minerals), and bioactive components (phytochemicals or polyphenols) in mango fruit gives it a high nutraceutical value.Several studies have been conducted in recent years employing the fruit's various components: peel, pulp, seed, and phytochemicals (Lo Galbo et al., 2021).
Various studies show that MGF possesses some antioxidant actions, a role in treating obesity, the therapeutic potential for osteoarthritis (Aboyewa et al., 2021) protection of the gastrointestinal tract, an antidiabetic role, and in vitro repressing properties on type-II 5α-reductase, modulatory response in the immune system, that is, maybe suppressive or stimulative, hepatoprotective, and cardioprotective effects in various diseases in rodents (Khoobchandani et al., 2021;Liu et al., 2021;Mubashir et al., 2022;Xiao et al., 2021).
It also shows photoprotective, analgesic, neuroprotective, anti-Alzheimer (Grauzdytė et al., 2019), and anti-allergic potential (Meng et al., 2023;Thitikornpong et al., 2019).The solubility of water for MGF is barely 0.111 mg/mL, which is much lower, limits its practical use, and consequently, no foodstuffs are in the marketplace.
Therefore, it is essential to scrutinize a project and particular distribution system for MGF to augment its medicinal effectiveness (Xiao et al., 2021).Figure 1 explains the structural presentation of MGF.
The word "cancer" portrays cells abandoned and anomalous growth, which can also disturb other organs.The dissemination of annoying growth of cancerous cells is known as metastasis, which may contribute to fatality.According to a study, cancer has the highest mortality rate, that is, responsible for 7 million deaths yearly (Plonski et al., 2021;Saeed et al., 2022;Sudduth et al., 2023).The most common cancers are prostate, skin melanoma, colon, breast, and uterine (Carminatti et al., 2023;Miller et al., 2019;Saeed et al., 2022).Cancer can be caused due to some internal and external factors.The internal agent is genetics, and the external one includes biological, chemical, and physical carcinogens, that is, bacteria or viruses, tobacco, alcohol, arsenic, ionizing, and ultraviolet radiations.
Older, inactive people with poor eating habits are more vulnerable to cancer than younger ones.Factors that can play a vital role in cancer prevention are the least exposure to sunlight, proper vaccination of viral infections, avoiding air pollution, eating fresh vegetables and fruits, and doing some physical activity daily (Cao et al., 2022;Leopold et al., 2022;Mitsogiannis et al., 2022).The risk of cancer can be reduced through timely diagnosis; early cancer treatment can increase the chances of survival (Ferlay et al., 2021) and appropriate patient care.It is supposed that every 30 days delay in surgery of cancer patients can increase the death rate to 6%-8% (Malagón et al., 2022).A study on outdated and corresponding medicine, 80% of people in under developed countries use plant-derived medications for health care (Rodriguez-Gonzalez et al., 2021).Traditional Chinese medicine can replace chemotherapy for better results in treating cancer (Sakthivel et al., 2023;Xiang et al., 2019;Zhang, 2023) and reduce side effects observed in radiotherapy (Nabil et al., 2018).
The number of phytochemical compounds filed to the Food and Drug Administration is significant in the oncological field.Several pieces of research demonstrated their effective antioncogenic, cytoprotective, non-progressive, and anti-invasive roles against various types of cancer cells by deficiently defined processes (El-Dawy et al., 2022;Elsayed et al., 2022;Rodriguez-Gonzalez et al., 2021;Tauseef ur et al., 2023).As an adjuvant to first-line medical therapy, nutrition-based strategies for preventing certain malignancies provide a significant advantage over presently utilized medical therapies (Saeed et al., 2022).In recent years, researchers have been particularly interested in the anticancer potential of natural chemicals obtained from fruits, plants, or chemically altered phytochemicals for use as fresh resources for developing novel cancer therapies (Adoho et al., 2022;Dai et al., 2023;Ijaz et al., 2023;Krishnaveni et al., 2023;Lo Galbo et al., 2021;Samota et al., 2023;Swantara et al., 2022).Carcinogenesis is a multi-factorial process involving several signaling pathways, and multitargeted phytochemicals are a prospective therapeutic area in cancer.A high antioxidant capacity and immunomodulatory phytochemicals are receiving significant scientific and clinical attention in developing innovative therapeutics for resilient drug malignancies such as castration-resistant prostate cancer (Drobner et al., 2023;Khoobchandani et al., 2021).
Chemoprevention is a new treatment that involves suppressing malignant development using natural herbal-based substances (Liu et al., 2021).
Also, it has been shown to influence apoptotic pathways by numerous targets (Aboyewa et al., 2021), reduce the deoxyribose nucleic acid DNA damage, and decrease the formation of the tumor as well as its further migration (Yu et al., 2019); its antitumor mode of action concerning neovascularization and tumor cell motility has yet to be thoroughly understood (Delgado-Hernández et al., 2020).MGF protects the mice against infection by increasing the frequency of delayed-type hypersensitivity reactions and the titer of humoral antibodies (Pourzafar et al., 2023;Shang et al., 2021).

| OBJEC TIVE S AND COLLEC TION OF DATA
This review article aims to investigate accessible scientific and evidence-based research about MGF (a phenolic compound mainly found in leaves, kernel, seed, and stems of mango) therapeutic potential against various cancers in its different forms, like powder, nanoparticles, injectables, and aqueous extracts, and to evaluate their findings for the better treatment of cancers and inhibit the further progression of tumors.Its efficacy for weight gain in different experimental units, prevention of tumor formation, minimizing cancer motility, and its use with other chemotherapeutic drugs to increase their efficiency, bioavailability, and retention time in the body are also discussed in this review.The main purpose of the review is to explore the MGF's mechanism of action in different pathways of certain cancers and to reveal the most appropriate form of MGF with its best-obtained results.The main objective of this review is to assess the beneficial and medicinal effects of MGF against cancer.The second is to obtain lower side effects on healthy cells and greater cytotoxic effects on tumor cells.The other objective is to evaluate appropriate methods to increase its bioavailability and solubility.The last objective is to unveil the pharmacological value of the bioactive component of mango waste in therapeutics.Moreover, current available scientific-based literature on the harmless and operative application of MGF for cancer therapy against different human cancer cell lines was collected and thoroughly studied for this review article.For data collection, powerful keywords like "mangiferin" OR "cancers" AND "anticancer agent" OR "mangiferin and cancer" have been searched at highly advanced search engines such as Google Scholar, Wiley, Scopus, and Science Direct.All possible research from 2017 to 2022 on cancer and MGF has been collected.However, the data obtained for "Improving Bioavailability of MGF" have some old literature before 2018.This review explains how MGF can be used to treat different cancers with fewer side effects, acceptable doses, and best outcomes, and this collected and confined description has yet to be found in past accessed reviews.

| IMPROVING THE B IOAVAIL AB ILIT Y OF MG F
MGF has low solubility as well as less oral bioavailability.These factors limit its use in therapy.Some experiments aimed to improve its bioavailability.In research, nanoprecipitation and solvent evaporation were used to design soft self-assembled nanoparticles encapsulated with phospholipid complexes (MPLC-SNPs) to enhance the antioxidant and biopharmaceutical potential of MGF.The solvent evaporation method was used to prepare the mangiferinphospholipon 90H complex (MPLC), and a central composite design was used for optimization.The nanoprecipitation method was used for the conversion of MPLC to MPLC-SNPs.In vivo, antioxidant studies and liver function tests showed that MPLC-SNPs notably conserved the antioxidant marker and CCl4-intoxicated liver marker enzymes compared to MGN-SNPs.The oral bioavailability of MPLC-SNPs was significantly increased tenfold by increasing the key pharmacokinetic parameters, including the area under the curve maximum serum concentration (C max ) and time for reaching up to maximum concentration (T max ).Consequently, MPLC-SNPs can be employed as a nanovesicle delivery system to improve MGF's antioxidant and biopharmaceutical potential (Telange et al., 2021).
Additionally, another examination showed that the MGFloaded nanostructured lipid carriers (MGF-NLC) method's physicochemical properties are characterized by particle size, polydispersity index, zeta potential, trapping efficiency, drug loading, morphological property, and crystalline nation.In vitro characteristics have been investigated with drug release from NLC gadgets, bodily stability, and corneal permeation via excised rabbit cornea.Moreover, in vivo, ocular tolerability is assessed through a modified Draize check and histological microscopy.Finally, the results showed a 5.69-fold increase in ophthalmic bioavailability compared to the MGF solution (MGN-SOL) (Liu et al., 2012).The aim of the existing is to research the pharmacokinetic profiles of MGF and mangiferin monosodium salt (MG-Na) in rat plasma by way of ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), which was then compared between the two companies.A suitable excessive sensitivity and selectivity UPLC-MS/MS technique was used to evaluate plasma pharmacokinetics in MGF and MG-Na using carbamazepine as an inner trend.The consequences showed that the area under the curve for MG-NA was more than MGF alone, and its bioavailability was 70%.There were statistically substantial variations in the pharmacokinetic parameters between MGF and MG-Na after a single oral administration at 100 mg/kg (Guo et al., 2019).
In another experiment, supercritical antisolvent techniques were used to enhance the bioavailability of MGF.In this method, N, N-dimethylformamide was used to work as a solvent and carbon dioxide as an antisolvent to make microparticles of MGF.
Results indicated that the bioavailability of MGF had been increased when utilized in microparticles than free MGF (Liu, Liu, et al., 2020;Nurhadi et al., 2022).Another study shows that when MGF is used with a complex of soy and phospholipid, it gives better bioavailability.This MGF complex was given to male albino rats in two doses, that is, 30 and 60 mg/kg BW, respectively.A soy phospholipid complex of MGF resulted in 9.75 times increased bioavailability than pure MGF and improved elimination half-life (t 1/2 el) (Bhattacharyya et al., 2014).Table 1 explains "increasing bioavailability by using a suitable dose" of MGF for its extensive use in treating various diseases.MGF has low solubility in GIT.
The research was conducted to improve its bioavailability and absorption by co-administrating three different potential absorption enhancers with MGF, that is, sodium deoxycholate (30 mg/ kg), TPGS (50 mg/kg), and Carbopol 974P (100 mg/kg).The most favorable results were obtained from Carbopol 974P in 7 times increased bioavailability.Carbopol 974P has some mucoadhesive and drug permeation properties at the paracellular level.Only Carbopol 974P is described in Table 1 because it showed the best effects (Xiaoli Wang et al., 2013).Crude MGF was compared with MGF-phospholipid complex to estimate their oral bioavailability.
Results suggested that the complex has more bioavailability than crude MGF and more solubility and permeability (Ma et al., 2014).
An increase in the bioavailability of MGF can be seen in Table 1.

| MECHANIS M OF AC TION
The mechanistic action of MGF is supported by several evidence- and decrease in tumor migration (movement to other cells) (Katti et al., 2018;Rodriguez-Gonzalez et al., 2021;Tan et al., 2018).MGF causes downregulation of matrix metallopeptidase 2 (MMP-2) and matrix metallopeptidase 9 (MMP-9), which result in decreased cellular proliferation (progression) and tumor motility; these processes ultimately lead to an increase in body weight (Zeng et al., 2020).In one study, MGF causes downregulation of the B-cell lymphoma (Bcl-2) gene and triggers the induction of Cas-3.These actions may play a role in apoptosis in cancerous cells.Furthermore, apoptosis causes a reduction in proliferation (Hu et al., 2022;Zhang & Wang, 2018).
In another study, MGF increases the production of ROS, which may lead to DNA damage and ultimately inhibit the further growth of cancer cells (Yu et al., 2019).Ultimately, all the above results cause cancer suppression, as shown in Figure 2.
MGF brings modulations to the immune system to play its anticancer role.It increases the secretions of interleukin-6 (IL-6) and IL-10.It decreases the IL-12 and tumor necrosis factor-alpha (TNF-∝), which jointly inhibit the angiogenesis of cancer cells and result TA B L E 1 Increasing the bioavailability of MGF by using a suitable dose. in cancer cell death (Hou et al., 2023;Khoobchandani et al., 2021;Sakthivel et al., 2023).In another study, it restricts c-c Motif Chemo Ligand 2 (CCL2), urokinase (activator of plasminogen), IL-6, of macrophages that lead to increase body weight and decrease in liver and spleen weights of the organism (Shang et al., 2021;Wen et al., 2022), as shown in Figure 3.
MGF has different mechanisms of action when used with other therapeutic drugs to treat cancer.In a study, gold-coated nanoparticles of MGF (MGF-AuNPs) and gold-coated nanoparticles of Honeybush (HB-AuNPs) were used with a chemotherapeutic drug named DOX, which collectively resulted in decreased cellular viability, that is, ability to work successively and increased cellular toxicity (Aboyewa et al., 2021).In other studies, MGF was used with Cisplatin, for example, an anticancer drug; it increased the sensitivity of cisplatin in the body and increased body weight while decreasing tumor size (He et al., 2019).Both these results have decreased cancer in the body, as shown in Figure 4.

| ANTITUMOR EFFEC TS OF MG F
Many types of research show that MGF has some antitumor effects against colorectal, oral, lung, ovarian, prostate, and hepatocellular tumors.Moreover, most studies are in vivo, but some are in vitro.
Few studies contain both in vivo and in vitro examinations.In some studies, pure MFG was used, but it has less retention time and some side effects.MGF was also used with other compounds conjunctively to increase efficacy and decrease side effects.MGF also synergizes with other compounds to reduce tumor size and inhibit tumor growth (Siripongvutikorn et al., 2023).
F I G U R E 3 MGF modulation of the immune system.

| In vivo studies
Several animals, like hamsters and male and female mice, The total number of experimental units was 24(n), which (hamsters) were divided into four groups in a way that six animals/groups.
Fourth group received alone-MGF orally in a dose of 50 mg per kg body weight (of hamsters) without receiving DMBA, and third group was orally treated with 50 mg/kg BW MGF floating on corn oil in the very first week before the exposure to mutant (carcinogen) also continued till the 14th week of study.The second and third groups were treated with 0.5% DMBA from 2 to 10 weeks of the experiment.The study results show a significant increase in weight gain in the third group, weight reduction in the second group, and no change in body weight in the fourth group.It was also noted that in group 3, immature tumor formation occurred, and mature tumors were formed in group 2. In the plasma and oral mucosa of group 3 hamsters, the levels of antioxidant enzymes and nonenzymatic antioxidants were near to normal than in all other groups (Liu et al., 2021).
The prostate tumor is solid as it does not have cysts (Katti et al., 2018).Its incidence and death rates depend on biological location (Culp et al., 2020;Djiwa et al., 2022;Kimura & Egawa, 2018;Rawla, 2019).Previous research indicates that radiotherapy was used to treat prostate cancers.In this study, researchers used radio- particles in the tumor also increased by more than 90% for a longer period with no leakage of nanoparticles through lymphatic ducts to non-target tissues (organs), which is a most important feature.
The results show that MGF-198AuNPs contain greater tumoricidal properties than all other nanoparticles for prostate cancer (Katti et al., 2018).Liver cancer is the second largest leading cause of cancer deaths worldwide (after lung cancer).At the same time, hepatocellular carcinoma is the most dominant malignancy of the liver, responsible for 85% of all liver malignancies (Li et al., 2023).Previous research shows that hyperactivity of the Wingless/Integrated (Wnt) signaling pathway enhances tumors' constant growth and motility.
MGF deactivates β-catenin, which is a controller of Wnt signaling.
In this study, Metastatic Hepatocellular Carcinoma Cell Line 97 (MHCC97L) of humans was used, which was tagged with luciferase (a reporter gene involved in oxidation).These cells were inoculated subcutaneously to the right side (between ribs and hips) of BALB/ mouse.After the development of tumors, they were shifted to the right hemispheres of the livers of other mice of different species (n = 5).MGF dose was 50 mg/kg body weight for 2 days.Results indicated that MGF inhibits tumor growth (Tan et al., 2018).MGF was used to assess its effects on mammary carcinoma.For this purpose, rats were selected as experimental units.DMBA was administered via subcutaneous route using a 0.5 mL single dose in the mammary glands of rats to induce carcinogenesis.As a result of carcinogenesis, increased incidence and tumor volume were observed along with the decreased level of antioxidant enzymes, increased thiobarbituric acid reactive substance concentration in plasma, increased levels of NF-κBp65, COX-2, iNOS, that is, inflammatory markers, and increased expression of Bcl-2 (antiapoptotic marker).When MGF was orally administered using 100 mg/kg BW/day, there was a significant reduction in the thiobarbituric acid reactive substance, and increased activity of antioxidant enzymes was seen.MGF inhibited NF-κBp65 activation, thus conquering inflammation and proliferation, and it boosted proapoptotic proteins (Kari et al., 2022;Ullah et al., 2022;Xin Wang et al., 2021).

| In vitro studies
Several cell lines were examined in in vitro experiments to check the antitumor effects of MGF.Surgical procedure is preferred over medicine to treat nonmetastatic colon cancer (Balasar et al., 2022;Coco & Leanza, 2022;Fei et al., 2018).The 95% pure MGF was used to assess its antitumor effects against CRC using cell line HT29 (ATCC The most dominant type of lung cancer is non-small cell lung cancer (NSCLC), which is a major cause of cancer deaths, and the existence rate for up to 5 years is less than 20% (Jiang & Zheng, 2022;Lin et al., 2020).Additionally, black individuals with NSCLC are significantly less likely to undergo surgery, that is, 49 for stages I-II and 16 for stage III, compared to 55 and 22% for white ones (Miller et al., 2022).Its ancient treatments include surgery, chemotherapy, Ovarian cancer (OC) is the third most malignant and prevalent gynecological cancer and is ranked as the fifth cause of female cancer deaths (Liu, Xu, et al., 2020;Raoofi et al., 2022).However, it also has a high survival rate but relapses in about 70% of cases because of drug resistance.OVCAR8 cells of Human ovarian adenocarcinoma were used in this study, which was highly resistant to cadmium, cisplatin, and platinum chemotherapy (He et al., 2019).Cisplatin is the most efficient physiotherapeutic drug but has less sensitivity to the body (Buhari et al., 2023;Liu et al., 2018) (Giaquinto, Miller, et al., 2022;Miller et al., 2021).It is more common in Black women than in any other.The incidence rate of breast cancer has increased (0.5% each year) in the last decade, but on the other side, its death rate has decreased (43% from 1989 to 2020) (Giaquinto, Sung, et al., 2022).The underlying causes of breast cancer are obesity, a sedentary lifestyle, and alcohol consumption (Islami et al., 2018).In this study, MGF extracts obtained from the bark, greens, and seed were found to be inhibitors of PKM2 through screening of the plant extract library.MDA-MB231 human triple-negative breast cancer (TNBC) cells were cultivated in (DMEM).MGF showed an inhibitory effect on the growth of TNBC.
Different concentrations of 90, 180, and 360 μg/mL of MGF extracts were used in a concentration-dependent manner to check the impact on PKM2 activity.Results indicated that PKM2 activity was lowest at 360 μg/mL.Ninety-four compounds derived from MGF were tested against three binding sites of PKM2 to validate their suppressive action.This research unveiled the novel modulators of PKM2.Further confirmation is still required because many enzymes of glucose metabolism can be targeted, but this investigation focused on PKM2 (Rasul et al., 2021).

| Inhibition of cellular proliferation and growth of cancerous cells
A study was designed to evaluate the effects of MGF against different cancers like cervical, breast, and lung cancers.Nanoparticles named magnetic microspheres loaded with MGF (MG-MS) were compared with free MGF.MCF-7, A549, and Hela cell lines were used in in vitro assays.Results indicated that MG-MS inhibited cellular proliferation more than free MGF.Cytotoxicity of MGF increased due to the presence of MS, which may improve the solubility of MGF in water.The release of MGF from nanoparticles was prolonged, which is helpful in action.So, MS can be used as a carrier of MGF to treat certain tumors (Xiao et al., 2021).
A progress report shared by the American Cancer Society revealed that 22,530 new cases and 13,980 deaths of OC were reported in 2019.Epithelial carcinoma is the most prevalent and lethal form of OC.The main purpose of this study was to check the anticancer role of MGF against epithelial carcinoma; the powder was used, which was dissolved in dimethyl sulfoxide (DMSO at 6 mg/mL).One of the epithelial carcinoma cell walls was and 20 mg/kg BW, respectively.Results revealed that a significant increase in the mouse's weight was observed, as well as a reduction in tumor growth and volume.In the enzyme-linked Immunosorbent assay (ELISA) technique, it was clear that MGF caused the downregulation of MMP2 and MMP9 in cancerous cells to decrease their progression (Zeng et al., 2020).Pancreatic cancer is ranked number seven for cancer deaths and is difficult to treat due to drug resistance and the side effects of chemotherapy (Yu et al., 2019).After diagnosis, only 1/5 of patients are selected for resection to cure it, but cancer can recur in them within 2 years (AlMasri et al., 2022).
Adjuvant therapy is used after the main treatment to destroy the leftover cancerous cells and is supposed to be the standard one to decrease the chances of recurrence (Conroy et al., 2018;Tempero et al., 2019).This research was conducted to check the anticancer effects of MGF against pancreatic cancer by using the Mia-PaCa2 was also observed (Yu et al., 2019).
Nowadays, degenerative as well as non-communicable diseases are prevalent in the world (Akhtar et al., 2023;Haroon et al., 2023;Wang & Hao, 2023).Due to increased drug resistance and relapse chances, plants are widely used to treat such diseases.They possess some bio-medical properties due to bioactive compounds like MGF.
TA B L E 2 Anticancer action of MGF based on human cell lines.This experiment was designed to explore different therapeutic activities, for example, antioxidant, antidiabetic, cytotoxicity of Aquilaria crassna leaves (ACE), and its bioactive compound MGF.To assess cytotoxic action, three cell lines, HepG2, HT-29, and MDA-MB-231, of human hepatocellular carcinoma, colorectal carcinoma, and breast cancer.Results suggested that the cytotoxic potential of MGF was 67.85% for liver cancer, 63.52% for OC, and 62.93% for breast cancer at 100 μg/mL, which was a maximum concentration and also

Colorectal cancer HT29 (ATCC HTB-38) of human colon adenocarcinoma
shows some free radical scavenging activity and antioxidant properties (Thitikornpong et al., 2019).The incidence of thyroid cancer is greater in women than men, while conjunctive therapy is used for its treatment due to its slow progression and poor differentiation.This experiment was conducted to investigate the anticancer and inhibitory action of MGF against thyroid cancer.Human thyroid cancer cell line TPC-1 (papillary cell line) was cultivated in DMEM-F12 (medium).Results showed that the functional capacity of TPC-1 was reduced, and the number of cells became half after 24 h using two and four micromole concentrations of MGF.Downregulation of Bcl-2, a protein that blocks apoptosis, and induction of Cas-3, a protein that causes the degradation of DNA, showed the induction of the apoptotic pathways.Moreover, expressions of proapoptotic proteins, that is, Bid, Bad, and Bax, were also increased.Decreased levels of proliferating cell nuclear antigen (PCNA), an antigen involved in the repairing and replicating DNA, revealed the decreased progression and survival of cancerous cells (Zhang & Wang, 2018).

| Overexpression of apoptotic proteins
Liver cancer is ranked fifth worldwide, with a mortality rate of over 9%.It is a silent cancer that spreads slowly and is also diagnosed at a later stage.The most familiar form of liver cancer is hepatocellular carcinoma (Nasrollahi et al., 2022;Yang et al., 2023).Some therapies (chemotherapy and radiotherapy) are commonly used to treat cancer but have a lot of toxic effects on cells other than cancer cells and also have side effects on the body.In this study, hepatocellular carcinoma was induced in Sprague-Dawley rats (immunodeficient rats having no NK, T, and B cells also vulnerable to infections) by using diethylnitrosamine (DEN, a carcinogen) in drinking water (0.01%) of rats for 12 weeks.After the 4 weeks of DEN, rats were treated with 50 mg MGF for 8 weeks.Histological examination of liver tissues and over-expressed apoptotic proteins indicated that MGF inhibited cancer induction.MGF showed anticarcinogenic effects by altering oxidative stress in DEN-induced carcinoma (Yang et al., 2019).

| Inhibition of phosphatidylinositol 3-kinase/ protein kinase B (PI3K/Akt) pathways
Gastric carcinoma, the type of cancer affecting the stomach's epithelial lining, is commonly found in both men and women (Du et al., 2018).The most favorable factors which can decrease its incidence are eating a healthy diet, less smoking in males, and decreased rate of H. pylori infection (Carioli et al., 2020).At the initial stage of cancer, laparoscopic gastrectomy is considered the most effective treatment of gastric cancer (Katai et al., 2019(Katai et al., , 2020;;Kim et al., 2019;Song et al., 2023).This study conducted a 3-( 4 cancer as a chemotherapeutic agent (Du et al., 2018).

| MODUL ATION OF IMMUNE RE SP ONSE S
Prostate cancer is the most prevalent cancer among males, causing mortality.In contrast, castration-resistant prostate cancer, commonly named CRPC, is a type of prostate cancer that also proliferates at low levels of testosterone hormone (the primary sex hormone of male) (Sekhoacha et al., 2022).Castration is when the testicle gland  (Khoobchandani et al., 2021;Pritam et al., 2021;Zhu & Dong, 2023).
Leukemia is a disease of blood-making tissues like lymphocytes and bone marrow, causing less production of blood RBCs, WBCs, and coagulating cells (plate cells).Acute myeloid leukemia (AML) is a disease of myeloid cells, self-regenerating, and immature cells that transform into monocytes (granulocytes).In AML, leukocytes (white blood cells) are produced less in fighting against invaders.
Chemotherapy and radiotherapy were considered perfect treatments for leukemia, but they have some adverse effects on normal cells.This research aimed to assess the effects of MGF on weight gain and the immune system.The WEHI-3 cell line was transferred in male mice, while doses of MGF were 40, 80, and 120 mg/kg body weight, respectively.Results suggested a subsequent increase in body weights, but decreased liver and spleen weights (spleen and liver became larger in leukemia) were also noticed.

| MG F IN COMB INATI ON WITH OTHER CHEMO THE R AP EUTIC DRUG S
OC is a major gynecological problem, and evidence-based studies suggest that YAP facilitates tumor formation (He et al., 2019).The incidence rate of OC is higher in Europe and North America than in Africa (Cabasag et al., 2022).Oral contraceptive pills can decrease the incidence of OC (Webb et al., 2017).Moreover, menopausal hormone therapy is directly linked with OC, but its use has decreased (Simin et al., 2020)

ACK N OWLED G M ENTS
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CO N FLI C T O F I NTE R E S T S TATE M E NT
None.
based researches.MGF has different mechanisms of action for different cancers.It depends upon the type of tumor and cancer and the dose of MGF.Here, we have concluded all the possible mechanisms of action in three ways.Moreover, reactions in each pathway are interconnected, as shown in Figures 2-4.In some studies, MGF causes changes in mitochondrial transcription, which may lead to decreased angiogenesis and tumor invasion.It also causes downregulation of Lymphoid enhancer-binding factor-1 (LEF-1 gene) as well as decreases the xanthone (glucose) metabolism in tumor cells; all these actions result in a reduction of tumor volume (size) and interferon-gamma(INFγ), leading to a decrease in angiogenesis (Delgado-Hernández et al., 2020).MGF causes an increase in a cluster of differentiation 3, which are co-receptors of T-cells (CD3Tcells), and the cluster of differentiation 19 B, which are components of B cells (CD19B), as well as decreases CD11b monocytes, and Mac3-macrophages (powerful macrophages) initiate phagocytosis were selected to study the antitumor effects of MGF.According to the 2018 Global Cancer Incidence, Mortality and Prevalence (GLOBOCAN)database, colorectal cancer (CRC) is the cause of 9% of cancer deaths and contributes to 10% of newly spotted cancer cases.CRC is both genders' most fatal and predominant tumor(Rodriguez- Gonzalez et al., 2021).Moreover, CRC is the second most common cancer in females and the third in males(Bray et al., 2018;Ishibashi et al., 2021;Liu et al., 2022).MGF was obtained as a fluent extract of MGF from the mango tree's greeneries, woof, and trunk.The tumor was induced through N-nitroso-N-methylurethane (NNMU) (a carcinogen) in cell line CT26.WT adenocarcinoma of the colon was then inoculated dermatologically on the right abaxial side of male Bagg and Albino Laboratory-based Bred/colony (BALB/c) mouse of age 6-8 weeks and 18 to 22 g weight in all the experiments.Then, animals were divided into five groups, that is, ten experimental units/groups.Pure MGF was prepared in 0.05% carboxymethylcellulose (CMC) and Cis-diamminedichloroplatinum (II) (CDDP; the generic name of cisplatin) in an antiseptic brine solution (0.9% sodium chloride) in different doses to the different groups, that is, 10, 50, and 100 mg/kg BW in a dose-dependent manner to assess tumor growth by monitoring size, length, and volume of the tumor.The reference drug for MGF was CDDP, provided to one of the five groups.Reduction in tumor size starts at day 22 after inoculation of the tumor.Results indicate that the reduction in tumor size was near 75% in a dose-dependent manner at 100 mg, and the overall reduction through reference drug (CDD) was 90%.812 genes were downregulated at 100 mg/kg body weight MGF dose with minor transcriptional changes in mitochondrial metabolic strain, iron maintenance, fatty acid metabolism, peroxisome proliferator-activated receptors, and regulators of lipid metabolism (PPARs), Glycoprotein 6 (GP6) signaling pathways and nuclear factor kappa B (NFkB) cause a decrease in movement (invasion) of the tumor and new blood vessels formation around tumor cells.MGF promotes decreased intra-tumoral and pre-tumoral blood supply levels (81% reduction at 200 μg/mL), and tumor volume and weight reduced by 84 and 73% at 200 μg/mL dose of MGF (Rodriguez-Gonzalez et al., 2021).Oral cancer is a malignant condition that includes head and neck carcinoma (HNC)(Liu et al., 2021); more than six lakh people have mouth cancer worldwide, and three lakhs die due to its severity.Risk factors for oral cancers are chewing betel nuts(Hung et al., 2020), overconsumption of tobacco, alcohol, and smoking.The tumor was induced through a carcinogen named 7,12-dimethylbenz[a]anthracene (DMBA) in oral squamous cell carcinoma of hamsters aged 8-10 weeks and weighing 80-120 g at the time of the experiment.
active MGF-198AuNPs instead of ionizing radioactive nanoparticles to check their antitumor effects on prostate cancer in men.Gold particles were produced through direct irradiation; one contained 1.55 mg of MGF.The findings revealed that these MGF-198AuNPs cause an 85% reduction in tumor volume.The retention time of F I G U R E 4 MGF's mechanism of action with other drugs.
HTB-38) of Human Colon adenocarcinoma, and the culture medium was McCoy's 5.The concentration of HT29 cells was 35,000 cells/ wells and treated with different applications of MGF like 1, 50, and 400 μM for cell feasibility assays.CT26 cells of mouse and HT29 human colon cells were treated with various MGF concentrations ranging from 10 to 400 μM.The results indicate no significant decrease or suppression of tumor invasion in HT29 cells.MGF overwhelms the vascular endothelial growth factor (VEGF) in the gene expression pathway, and it stimulates prometastatic motility in mouse cells and proangiogenic motility in human cells (Rodriguez-Gonzalez et al., 2021).
radiation therapy.The cell lines used in the study were NCI-H460 (HTB-177), NCI-H520 (HTB-182), and A549(CCL-185) for human large cell lung cancer, human squamous cell carcinoma, and nonsmall cell carcinoma; 98% pure MGF was used in the study.The tumor was induced in cells through lipopolysaccharide (carcinogen).The in vitro results reveal that MGF inhibits the growth of tumor cells, inhibits expression of vimentin, decreases migration activity of NSCLC, decreases secretion of Interleukin 1 beta (IL-1β), and reconciled protein levels of Period Circadian Regulator 1 (PER1) and NLR family pyrin domain containing 3 (NLRP3) in NSCLC(Lin et al., 2020).A comparative experiment was conducted to check the effectiveness of silver-coated nanoparticles of MGF (AgNPs) over pure MGF against bone cancer (Osteosarcoma).AgNPs were synthesized, ranging from 25.30 to 40.79 nm in size.Different concentrations of pure MGF and AgNPs were utilized, that is, 10, 25, 50, and 100 μg/ mL against Human MG-63 (osteosarcoma cells) in rats.Results suggested that all AgNPs and pure MGF concentrations showed significant cytotoxic potential against cancerous cells.However, in the case of normal stem cells of mesenchyme, 50 μg/mL of pure MGF and 10 μg/mL of AgNPs were compared.Both concentrations are considered toxic to cancerous cells, but results indicated that these levels were safe for normal cells.Hence, AgNPs can be used to distribute MGF to cancerous cells better.AgNPs have more cytotoxic potential in bone cancer than pure MGF(Othman & Seka, 2019).
cell line and normal cell line HTRET-HPNE to check how much MGF is deadly for them.Results indicated that MGF inhibited the growth of cancerous cells, and the inhibitory concentration of MGF for the cancerous cell was 10 μM, but it was 75 μM for normal cells.There were increased expressions of light chain 3 II (LC3 II), light chain 3 (LC3), and Beclin-1 (Becn1), indicating self-eating (autophagy) of Mia-PaCa2 cells.MGF caused apoptosis (programmed cell death) due to the upregulation of proteins Bcl-2 and Bax, which act as apoptosis biomarkers.Moreover, MGF increases the endogenous production of ROS at 20 μM concentration, which causes damage to the DNA of cancer cells.A significant reduction in mitochondrialmediated protein (MMP) confirmed ROS production, and cell arrest or 800 μg/mL PER1 was less expressed in LPS-stimulated NSCLC cells, MGF in combination increases PER1 expression Lin et al. (2020) Skin cancer B16F10 (B16F10 cell line) melanoma and EA.hy 926 endothelial cells of the human umbilical vein Medium (DMEM) 240 μM Inhibition of cell migration, non-cytotoxic effects, inhibition of endothelial growth, 50% inhibition in capillary growth, and 70% ,5-dimethylthiazol-2yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay to investigate the effects of MGF on cell functionality and progression.Two cell lines of gastric lining, SGC-7901 and BCG-823, were used to check their apoptotic rates by investigating the expressions of proteins related to apoptosis (a planned cell death).Results indicated that MGF repressed the cellular growth of both cells (SGC-7901 and BCG-823) in a time-and dose-dependent way.The IC50 values were gradually decreased from 16 to 4.79 μ mole/liter for SGC-7901 cells which were manifested to MGF for 24, 48, and 72 h.MGF caused a decrease in the expressions of Bcl-2, B-cell lymphoma-extra-large (Bcl-xL) and induced myeloid leukemia cell differentiation protein (Mcl-1) and increased expressions of Bad, Bax along with caspase-3 and 9 in SGC-7901 cells.This research concludes that MFG decreases the growth, progression, and new blood vessel formation in gastric cell lines by inhibiting PI3K/Akt pathways.So, MGF can safely treat stomach cannot produce a normal testosterone level.The tumor microenvironment plays a vital role in the function of immunity.In this experiment, MGF-AuNPs were utilized by tumor-containing mice to check their immunomodulation and effects on prostate cancer.Results showed that these nanoparticles had increased IL-12 and TNFα (antitumor chemicals) levels with a simultaneous decrease in IL-6 and IL-10 (pre-tumor cytokines).Observations indicated that IL-12 increased 10 times, TNFα increased 10 times, and tumor-supporting cytokines decreased by 2 times.MGF-AuNPs showed no toxicity toward non-cancerous cells due to less density of laminin receptors in normal cells but increased toxicity to cancerous cells due to overexpression of laminin receptors.MGF targeted splenic macrophages (which perform a phagocytic activity in the blood) by targeting the NFkB signaling pathway, which makes the connection between danger signals and pathogenic signals of a cell.There was inhibition of angiogenesis near cancer cells, which resulted in cell death.In the end, the tumor growth stopped, and a reduction in tumor volume also occurred Increased CD3T-cell and CD19 B cells were seen, but CD11b monocyte and Mac-3 macrophages (markers of macrophages) were reduced.Moreover, decreased phagocytosis of macrophages by peripheral blood mononuclear cells (PBMC).Splenocytes (WBCs of the spleen) were used to check the cytotoxic activity of NK cells and MGF, which did not affect the progression of T and B lymphocytes.The survival rate of leukemia mice depended upon the given dose of MGF, which was increased at a high dose of MGF(Shang et al., 2021).Melanoma is one of the most dangerous and deadliest forms of skin cancer, having metastatic characteristics, a condition in which the primary tumor loses its cells that make a new tumor.Its treatments have not increased the survival rates of patients.This study was designed to evaluate the antiangiogenic effects of MGF and explore the hidden mechanism of action.Two cell lines of human A549 (epithelial line) and EA.hy 926 hybridoma (umbilical vein line) were used.Results revealed that MGF has anti-inflammatory effects and interacts with lipid and calcium pathways to inhibit the release of chemicals through NFkB.Matrix metalloprotease 19, placental growth factor (part of VEGF), and vascular endothelial growth factor receptor 2 play a crucial role in forming new blood vessels (angiogenesis), and MGF inhibited migration of cancerous cells.IL-6 (involved in inflammation), INFγ (cytokine), urokinase (convert plasminogen into plasmin), and CCL2 (monocyte chemoattractant) were also restricted to the site of the tumor as well as decreased the process of metastasis.All these actions hindered the formation of the new capillary tube for angiogenesis in human blood vessels of the placenta (in vitro) and a chicken's egg (in vivo).Thus, the described experimental research has explained the inhibition of angiogenesis by modulation of immune cells(Delgado-Hernández et al., 2020).
(He et al., 2019)ffects on tumor volume.Results indicated that conjunctive therapy (MGF + Cisplatin) decreases tumor size (volume), increases mice's body weights, increases life span, and enhances the sensitivity of tumor cells to cisplatin.Therefore, combined with MGF, cisplatin can treat tumors resistant to cisplatin(He et al., 2019).Table3explains the "anticancer action of MGF based on animal studies" to check the efficiency of MGF in handling cancers and depicts its mechanism of action for different cancers.Anticancer action of MGF based on animal studies.
(Aboyewa et al., 2021)human ovarian cells, OVCAR8, were introduced to female mice (N = 60) weighing 16-18 g.MGF + cisplatin (50 mg and 10 mg/kg BW) was the main phytochemical to prostate cancer cell lines.Both particles were stable in water.Both nanoparticles were tested with DOX in cancerous colon cells, and results showed that the efficiency of cells decreased from 40% to 70% and toxicity was greater at higher concentrations.So, MGF-AuNPs and HB-AuNPs can be synergistically used with DOX and may give better results in treating cancers(Aboyewa et al., 2021).9|CON CLUS IONSfor humans are needed.Previous literature revealed that pure MGF has low solubility in water, less bioavailability, and the least distribution to cancerous cells.Scientific data regarding its effective dose for greater cytotoxic effects still need to be included.Certain techniques are available to increase its rate of distribution and bioavailability, like nanoparticles or combining with other drugs, but more TA B L E 3